title: Myocardial ER chaperone activation and protein degradation occurs due to synergistic, not individual, cold and hypoxic stress.
abstract: Environmental stress at high altitude affects the myocardium at the physiological and molecular level. Characterized by hypobaric hypoxia and low temperatures, the cumulative impact of these stressors on the protein folding homeostasis in the heart is yet unexplored. The present study evaluates the collective effect of cold and hypoxia on the myocardial protein oxidation and activation of the endoplasmic reticulum (ER) stress response. Adult rats were exposed to either a singular acute stress of cold (10 °C; C), hypobaric hypoxia (7620 m; H) or simultaneously to both cold and hypobaric hypoxia (CH) for 6 h. Hypoxic stress amplified the free radical generation in H and CH groups, leading to enhanced HIF-1α expression. Coupled to cold stress, reduced oxygen availability caused substantial protein oxidative modifications, as well as cardiac tissue injury and matrix remodeling, evident in the histological staining. Presence of oxidized proteins caused a significant upregulation in expression of ER chaperones GRP78 and PDI in the cold hypoxia exposed animals. Enhanced proteolytic activity signaled the removal of misfolded proteins. Linked intricately to cellular stress response, cell survival kinases were expressed higher in CH group; however apoptotic CHOP (C/EBP homologous protein) expression remained unaltered. Administration of ER stress inducer, tunicamycin along with cold hypoxic stress, caused a discernible increase in protein oxidation and GRP78 expression, along with a significant elevation in proteasome and apoptotic activity. Highlighting the significance of a synergistic, rather than individual, effect of low oxygen and temperature on the protein folding machinery, our study provides evidence for the activation of ER stress response in the myocardium under acute high altitude stress.
authors.affiliation: Cellular Biochemistry Group, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110054, India.
authors.forename: Kanika
authors.initials: K
authors.lastname: Jain
authors.forename: Geetha
authors.initials: G
authors.lastname: Suryakumar
authors.forename: Rajendra
authors.initials: R
authors.lastname: Prasad
authors.forename: Som Nath
authors.initials: SN
authors.lastname: Singh
authors.forename: Lilly
authors.initials: L
authors.lastname: Ganju
mesh_terms: D000818:Animals; D017209:Apoptosis; D003080:Cold Temperature / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D006360:Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046988:Proteasome Endopeptidase Complex; D019704:Protein Disulfide-Isomerases; D051742:Transcription Factor CHOP; D014415:Tunicamycin; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C497444:Hif1a protein, rat
keywords: Chaperones; Cold; ER stress; Heart; Hypobaric hypoxia